Translating autism

Researchers at McGill University have mouse data
showing a causal link between eIF4E-mediated
translational dysregulation and autism-related deficits. The group also
corrected the dysregulation-and the associated autistic phenotype-with a small
molecule.1

The
McGill group, led by Nahum Sonenberg, has been studying the role of eukaryotic translation initiation factor 4E
(eIF4E) in protein synthesis for over three decades and has primarily focused
on the factor's relevance in cancer. eIF4E binds to the cap structure on mRNA
and helps to initiate the translation of the mRNA. Sonenberg is a professor in
the Department of Biochemistry and at the Rosalind and Morris Goodman Cancer
Research Centre at McGill.

Separately,
a 2009 study from a research group in the U.K. showed an association between
mutations that increased eIF4E promoter activity and autism.6

With
multiple studies pointing to eIF4E-dependent processes in autism, the McGill
group sought to determine whether dysregulation of eIF4E activity itself could
cause an autistic phenotype. Indeed, past studies suggested that dysregulated
translation of mRNA could be an underlying cause of autism7 but
never showed a causal relationship.

In
a new study published in Nature, the McGill researchers showed that
increasing eif4e activity in mice-by knocking out the gene encoding an eif4e
repressor called eif4e binding protein 2 (eif4ebp2)-led to autism-associated
electrophysiological abnormalities and behaviors.

In
these mice, as well as mice that overexpressed eif4e, translation of neuroligin
proteins was greater than that seen in wild-type controls. Alterations in
neuroligin signaling occur in autism.8,9

In
the mouse models, a small molecule inhibitor of eIF4E signaling called 4EGI-1 reversed the
electrophysiological abnormalities and decreased autistic behaviors compared
with vehicle. Knockdown of neuroligin 1 (Nlgn1) had similar effects.

Importantly,
inhibition of eif4e and Nlgn1 activity did not affect electrophysiological and
behavioral parameters in wild-type mice.

"The
study is of particular interest for me because it provides strong evidence
directly supporting the 'troubled translation' hypothesis that Mark Bear and I
proposed in 2008, where we suggested that dysregulation of translation may be a
core pathophysiological mechanism in autism," said Raymond Kelleher, an
assistant professor of neurology at Harvard Medical School and a principal
investigator at the Center for Human Genetic Research at Massachusetts General Hospital.

Kelleher
said the new data also draw a direct link between translational dysregulation
and the regulation of the balance of excitatory and inhibitory synaptic
transmission by neuroligins, which is another candidate pathophysiological
mechanism in autism.

Eric
Klann, a professor in the Center for Neural Science at New York University, said the results
are consistent with observations from ongoing work from his lab, which is
investigating excessive eIF4E translation as a molecular mechanism underlying
autism. He added that his group has been working with similar mouse autism
models and with 4EGI-1.

Klann
noted that his group has a complementary paper in the press that further
solidifies the causal relationship between eIF4E-mediated translational
dysregulation and autism.

"Our
work and the Sonenberg data show that exaggerated eIF4E-dependent translation
will cause synaptic and behavioral abnormalities consistent with autism,"
he told SciBX.

Validation
needed

The findings now need to be validated in
mice carrying mutations in genes known to cause autism and with more drug-like
inhibitors of eIF4E-mediated protein translation than 4EGI-1.

A
group at Harvard Medical School first identified 4EGI-1 in 2007 as a small
molecule that inhibits translation of mRNA by disrupting the association
between eIF4E and eIF4g (EIF4G).10 However, the
researchers noted in their study that the compound does not have the potency
necessary for development as a drug candidate.

Moreover,
it is still unclear which subset of patients with autism should be targeted.
Klann said fragile X-associated autism could be the place to start, as
dysregulated mRNA translation also is seen in mouse models of fragile X
syndrome.

About
15%-30% of patients with fragile X syndrome also have autism.7

Klann
added that there already are multiple companies trying to target the
eIF4E-regulated translational axis and related axes in cancer. "Some of
the compounds these companies are developing could potentially cross the blood
brain barrier and could thus be suitable for use in patients with autism,"
he told SciBX.

The
generic antiviral ribavirin also inhibits oncogenic eIF4E activity and has been
tested in an investigator-led Phase II trial in patients with acute myelogenous
leukemia (AML).11,12 The researchers reported 5 responses and 4
cases of stable disease among 11 evaluable patients.

Kelleher
wanted to see the McGill team's findings validated in other mouse autism
models.

"It
will be important to determine whether the mechanisms defined in this study
apply to known genetic causes of autism-that is, whether known genetic causes
of autism lead to dysregulation of cap-dependent translation and/or neuroligin
expression," he told SciBX. "Similarly, it will be important
to test whether partial inhibition of cap-dependent translation or knockdown of
specific neuroligins can reverse synaptic and behavioral deficits in mouse
models of known genetic causes of autism."

Sonenberg
said his group is developing mice with eif4ebp2 knocked out in specific brain
regions. His team also is trying to develop conditional knockout mice to
determine whether loss of eif4ebp2 at different time points in early life would
lead to the autistic phenotype.

Klann's
group is now trying to determine whether targeting eif4e in fragile X mouse
models would be able to correct the associated autistic behaviors. The team
also is trying to develop a method to measure the translation of various
proteins in the mouse autism models, which will help to identify common
dysregulated proteins across the multiple models.

Finally,
Klann said his group has been contacted by companies interested in testing
compounds that inhibit the eIF4E translational regulatory pathway in the mouse autism
models being used by his group.

The
findings reported in Nature are unpatented. The mouse models are
available for licensing.

Access this BioCentury Innovations article Cover Story for your individual use via a permanent link that allows you to read or print the article, and any sub-articles, charts, tables and/or graphs related to this specific story: $50.
The article link will be posted on the purchase transaction web page, and also emailed to you with your purchase confirmation.

Purchase This Article for Limited One-Time Distribution and Posting to Your Website :

Receive a formatted PDF reprint of this article, including any sub-articles, charts, tables and/or graphs related to this specific article, with rights for limited one-time redistribution and posting to your website: $750. Please allow 24-48 hours for delivery.

Purchase Options

Purchase this article for individual use $50 USDPurchase this article for limited one-time distribution and website posting $750 USD